WO1996019988A1 - Monomeres de 4,4-(disubstitue)cyclohexan-1-oles et composes apparentes - Google Patents

Monomeres de 4,4-(disubstitue)cyclohexan-1-oles et composes apparentes Download PDF

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Publication number
WO1996019988A1
WO1996019988A1 PCT/US1995/016711 US9516711W WO9619988A1 WO 1996019988 A1 WO1996019988 A1 WO 1996019988A1 US 9516711 W US9516711 W US 9516711W WO 9619988 A1 WO9619988 A1 WO 9619988A1
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WO
WIPO (PCT)
Prior art keywords
cyclopentyloxy
methoxyphenyl
cis
cyclohexan
ylethynyl
Prior art date
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PCT/US1995/016711
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English (en)
Inventor
Siegfried B. Christensen, Iv
Joseph M. Karpinski
M. Dominic Ryan
Paul E. Bender
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Smithkline Beecham Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Priority to MX9704729A priority Critical patent/MX9704729A/es
Priority to JP8520529A priority patent/JPH10511658A/ja
Priority to UA97066495A priority patent/UA48157C2/uk
Priority to AT95944363T priority patent/ATE306260T1/de
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to SK795-97A priority patent/SK79597A3/sk
Priority to DE69534518T priority patent/DE69534518D1/de
Priority to BR9510257A priority patent/BR9510257A/pt
Priority to NZ301096A priority patent/NZ301096A/xx
Priority to US08/860,287 priority patent/US5891883A/en
Priority to EP95944363A priority patent/EP0794774B1/fr
Priority to AU46433/96A priority patent/AU703246C/en
Publication of WO1996019988A1 publication Critical patent/WO1996019988A1/fr
Priority to FI972676A priority patent/FI972676A/fi
Priority to NO972906A priority patent/NO972906L/no
Priority to BG101716A priority patent/BG62034B1/bg

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Definitions

  • the present invention relates to novel 4,4-(disubstituted)cyclohexan-1-ols monomers and related compounds, pharmaceutical compositions containing these compounds, and their use in treating allergic and inflammatory diseases and for inhibiting the production of Tumor Necrosis Factor (TNF).
  • TNF Tumor Necrosis Factor
  • Bronchial asthma is a complex, multifactorial disease characterized by reversible narrowing of the airway and hyperreactivity of the respiratory tract to external stimuli.
  • Cyclic AMP adenosine cyclic 3',5'-monophosphate
  • Cyclic AMP has been shown to be a second messenger mediating the biologic responses to a wide range of hormones, neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973].
  • adenylate cyclase is activated, which converts Mg+2-A TP to cAMP at an accelerated rate.
  • Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of c AMP would produce beneficial effects including: 1) airway smooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage activation.
  • beneficial effects including: 1) airway smooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage activation.
  • phosphodiesterase should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammarory cells.
  • the principal cellular mechanism for the inactivation of c AMP is hydrolysis of the 3'-phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs).
  • PDE IV cyclic nucleotide phosphodiesterase
  • PDE IV inhibitors are markedly potentiated when adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids, as would be the case in vivo.
  • PDE IV inhibitors would be effective in the asthmatic lung, where levels of prostaglandin E2 and prostacyclin (activators of adenylate cyclase) are elevated.
  • Such compounds would offer a unique approach toward the pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on the market
  • the compounds of this invention also inhibit the production of Tumor Necrosis
  • TNF Tumor Factor
  • rheumatoid arthritis rheumatoid spondylitis
  • osteoarthritis gouty arthritis and other arthritic conditions
  • sepsis septic shock, endotoxic shock, gram negative sepsis
  • toxic shock syndrome adult respiratory distress syndrome
  • cerebral malaria chronic pulmonary inflammatory disease
  • silicosis pulmonary saicoidosis
  • bone resorption diseases reperfusion injury
  • graft vs a serum glycoprotein.
  • allograft rejections fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to human acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis, in addition to a number of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosis.
  • AIDS acquired immune deficiency syndrome
  • AIDS AIDS
  • ARC AIDS related complex
  • keloid formation scar tissue formation
  • Crohn's disease Crohn's disease
  • ulcerative colitis ulcerative colitis
  • pyresis in addition to a number of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosis.
  • HIV Immunodeficiency Virus
  • HIV-1 HIV-1
  • HIV-2 HIV-2
  • HIV-3 HIV-3
  • HIV-1 HIV-1
  • HIV-2 HIV-2
  • HIV-3 HIV-3
  • HIV entry into the T lymphocyte requires T lymphocyte activation.
  • Viruses such asHIV-1 or HIV-2 infect T lymphocytes after T cell activation and such virus protein expression and/or replication is mediated or maintained by such T cell activation.
  • the T lymphocyte Once an activated T lymphocyte is infected with HIV, the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/orHIV replication.
  • Cytokines are implicated in activated T-cell-mediated HIV protein expression and/or virus replication by playing a role in maintaining T
  • lymphocyte activation Therefore, interference with cytokine activity such as by inhibition of cytokine production, notably TNF, in an HIV-infected individual aids in limiting the maintenance of T cell activation, thereby reducing the progression of HIV infectivity to previously uninfected cells which results in a slowing or elimination of the progression of immune dysfunction caused by HIV infection.
  • Monocytes, macrophages, and related cells, such as kupffer and glial cells have also been implicated in maintenance of the HIV infection. These cells, like T cells, are targets for viral replication and the level of viral replication is dependent upon the activation state of the cells. [See Rosenberg et al., The Immunopathogenesis of HIV Infection, Advances in Immunology, VoL 57, 1989].
  • Monokines such as TNF have been shown to activate HIV replication in monocytes and/or macrophages [See Poli et al., Proc. Natl. Acad. Sci., 87:782-784, 1990], therefore, inhibition of monolrine production or activity aids in limiting HIV progression as stated above for T cells.
  • TNF has also been implicated in various roles with other viral infections, such as the cytomegalovirus (CMV), influenza virus, adenovirus, and the herpes virus for similar reasons as those noted.
  • CMV cytomegalovirus
  • influenza virus influenza virus
  • adenovirus adenovirus
  • herpes virus herpes virus
  • TNF is also associated with yeast and fungal infections. Specifically Candida albicans has been shown to induce TNF production in vitro in human monocytes and natural killer cells. [See Riipi et al.. Infection and Immunity, 58(9):2750-54, 1990; and Jafari et al.. Journal of Infectious Diseases, 164:389-95, 1991. See also Wasan et al., Antimicrobial Agents and Chemotherapy, 35,(10):2046-48, 1991; and Luke et al.. Journal of Infectious Diseases, 162:211-214,1990].
  • R 1 is -(CR 4 R 5 ) n C(O)O(CR 4 R 5 ) m R 6 , -(CR 4 R 5 ) n C(O)NR 4 (CR 4 R 5 ) m R 6 , -(CR 4 R 5 ) n O(CR 4 R 5 ) m R 6 , or -(CR 4 R 5 ) r R 6 wherein the alkyl moieties unsubstituted or substituted with one or more halogens;
  • n 0 to 2;
  • n 0 to 4.
  • r is 0 to 6;
  • R 4 and R 5 are independently selected hydrogen or C 1-2 alkyl;
  • R 6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC 1-3 alkyl, halo substituted aryloxyC 1-3 alkyl, indanyl, indenyl, C 7-11 polycycloalkyl,
  • X is YR 2 , fluorine, NR 4 R 5 , or formyl amine
  • Y is O or S(O) m' ;
  • n' 0, 1, or 2;
  • X 2 is O or NR 8 ;
  • X 3 is hydrogen or X
  • X4 is H, R 9 , OR 8 , CN, C(O)R 8 , C(O)OR 8 , C(O)NR 8 R 8 , or NR 8 R 8 ;
  • R 2 is independently selected from -CH 3 or -CH 2 CH 3 optionally substituted by 1 or more halogens;
  • s is 0 to 4.
  • W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms;
  • R 3 is COOR 14 , C(O)NR 4 R 14 or R 7 ;
  • Z is OR 14 , OR 15 , SR 14 , S(O) m' R 7 , S(O) 2 NR 10 R 14 , NR 10 R 14 ,
  • Y is O or S
  • R 7 is -(CR 4 R 5 ) q R 12 or C 1-6 alkyl wherein the R 12 or C 1-6 alkyl group is unsubstituted or substituted one or more times by methyl or ethyl unsubstituted or substituted by 1-3 fluorines, -F, -Br, -Cl, -NO 2 , -NR 10 R 11 , -C(O)R 8 , -CO 2 R 8 , -O(CH 2 ) 2-4 OR 8 , -O(CH 2 )qR 8 , -CN, -C(O)NR 10 R 11 , -O(CH 2 ) q C(O)NR 10 R 11 , - O(CH 2 ) q C(O)R 9 , -NR 10 C(O)NR 10 R 11 , -NR 10 C(O)R 11 , -NR 10 C(O)OR 9 , -NR 10 C(O)R 13 , -
  • q 0, 1, or 2;
  • R 12 is R 13 , C 3 -C 7 cycloalkyl, or an unsubstituted or substituted aryl or heteroaryl group selected from the group consisting of (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, and phenyl;
  • R 8 is independently selected from hydrogen or R 9 ;
  • R 9 is C 1-4 alkyl optionally substituted by one to three fluorines
  • R 10 is OR 8 or R 11 ;
  • R 1 1 is hydrogen, or C 1-4 alkyl unsubstituted or substituted by one to three fluorines; or when R 10 and R 1 1 are as NR 10 R 1 1 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and one or more additional heteroatoms selected from O, N, or S;
  • R 13 is a substituted or unsubstituted heteroaryl group selected from the group consisting of oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, and thiadiazolyl, and where R 13 is substituted on R 12 or R 13 the rings are connected through a carbon atom and each second R 13 ring may be unsubstituted or substituted by one or two C 1-2 alkyl groups unsubstituted or substituted on the methyl with 1 to 3 fluoro atoms;
  • R 14 is hydrogen or R 7 ; or when R 8 and R 14 are as NR 8 R 14 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and one or more additional heteroatoms selected from O, N, or S;
  • R 15 is C(O)R 14 , C(O)NR s R 14 , S(O) q NR s R 14 or S(O) q R 7 where q is 0, 1 or 2; provided that:
  • R 7 is not C 1-4 alkyl unsubstituted or substituted by one to three fluorines; or the pharmaceutically acceptable salts thereof.
  • This invention also relates to the pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier or diluent
  • the invention also relates to a method of mediation or inhibition of the enzymatic activity (or catalytic activity) of PDE IV in mammals, including humans, which comprises administering to a mammal in need thereof an effective amount of a compound of Formula (I) as shown below.
  • the invention further provides a method for the treatment of allergic and inflammatory disease which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of Formula (I).
  • the invention also provides a method for the treatment of asthma which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of Formula (I).
  • This invention also relates to a method of inhibiting TNF production in a mammal, including humans, which method comprises administering to a mammal in need of such treatment, an effective TNF inhibiting amount of a compound of Formula (I).
  • This method may be used for the prophylactic treatment or prevention of certain TNF mediated disease states amenable thereto.
  • This invention also relates to a method of treating a human afflicted with a human immunodeficiency virus (HIV), which comprises administering to such human an effective TNF inhibiting amount of a compound of Formula (I).
  • HAV human immunodeficiency virus
  • Compounds of Formula (I) are also useful in the treatment of additional viral infections, where such viruses are sensitive to upregulation by TNF or will elicit TNF production in vivo.
  • compounds of Formula (I) are also useful in treating yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo.
  • This invention also relates to a method of mediating or inhibiting the enzymatic activity (or catalytic activity) of PDE IV in a mammal in need thereof and to inhibiting the production of TNF in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I).
  • Phosphodiesterase IV inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases including: asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic
  • PDE TV inhibitors are useful in the treatment of diabetes insipidus and central nervous system disorders such as depression and multi-infarct dementia.
  • viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF inhibitors of Formula (I).
  • viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV). influenza, adenovirus and the Herpes group of viruses, such as, but not limited to, Herpes zoster and Herpes simplex.
  • CMV cytomegalovirus
  • influenza adenovirus
  • Herpes group of viruses such as, but not limited to, Herpes zoster and Herpes simplex.
  • This invention more specifically relates to a method of treating a mammal, afflicted with a human immunodeficiency virus (HIV), which comprises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (I).
  • HAV human immunodeficiency virus
  • TNF mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections.
  • viruses include, but are not limited to feline
  • FMV immunodeficiency virus
  • retro viral infection such as equine infectious anemia virus, caprine arthritis virus, visna virus, maedi virus and other lentiviruses.
  • the compounds of this invention are also useful in treating yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo.
  • a preferred disease state for treatment is fungal meningitis.
  • the compounds of Formula (I) may be administered in conjunction with other drugs of choice for systemic yeast and fungal infections.
  • Drugs of choice for fungal infections include but are not limited to the class of compounds called the polymixins, such as Polymycin B, the class of compounds called the imidazoles, such as clotrimazole, econazole, miconazole, and ketoconazole; the class of compounds called the triazoles, such as fluconazole, and itranazole, and the class of compound called the Amphotericins, in particular Amphotericin B and liposomal Amphotericin B.
  • polymixins such as Polymycin B
  • imidazoles such as clotrimazole, econazole, miconazole, and ketoconazole
  • triazoles such as fluconazole, and itranazole
  • Amphotericins in particular Amphotericin B and liposomal Amphotericin B.
  • the compounds of Formula (I) may also be used for inhibiting and/or reducing the toxicity of an anti-fungal, anti-bacterial or anti-viral agent by administering an effective amount of a compound of Formula (I) to a mammal in need of such treatment
  • a compound of Formula (I) is administered for inhibiting or reducing the toxicity of the Amphotericin class of compounds, in particular Amphotericin B.
  • C 1-3 alkyl C 1-4 alkyl
  • C 1-6 alkyl or “alkyl” groups as used herein is meant to include both straight or branched chain radicals of 1 to 10, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
  • Alkenyl means both straight or branched chain radicals of 1 to 6 carbon lengths, unless the chain length is limited thereto, including but not limited to vinyl, 1-propenyl, 2-propenyl, or 3-methyl-2-propenyl.
  • cycloalkyl or "cycloalkyl alkyl” means groups of 3-7 carbon atoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl, or cyclohexyl.
  • the alkyl chain is meant to include both straight or branched chain radicals of 1 to 4 carbon atoms.
  • Heteroaryl means an aromatic ring system containing one or more
  • Halo means all halogens, i.e., chloro, fluoro, bromo, or iodo.
  • TNF mediated disease or disease states means any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another cytoldne to be released, such as but not limited to IL-1 or IL-6.
  • TNF-ß also known as lymphotoxin
  • TNF- ⁇ also known as cachectin
  • both TNF- ⁇ and TNF-ß are inhibited by the compounds of the present invention and thus are herein referred to collectively as 'TNF" unless specifically delineated otherwise.
  • TNF- ⁇ is inhibited.
  • Cytoldne means any secreted polypeptide that affects the functions of cells, and is a molecule which modulates interactions between cells in immune, inflammatory, or hematopoietic responses.
  • a cytoldne includes, but is not limited to, monokines and lympho-rines regardless of which cells produce them.
  • the cytokine inhibited by the present invention for use in the treatment of a HIV-infected human must be a cytoldne which is implicated in (a) the initiation and/or maintenance of T cell activation and/or activated T cell-mediated HIV gene expression and/or replication, and/or (b) any cytokine-mediated disease associated problem such as cachexia or muscle degeneration.
  • his cytokine is TNF- ⁇ .
  • All of the compounds of Formula (I) are useful in the method of inhibiting the production of TNF, preferably by macrophages, monocytes or macrophages and monocytes, in a mammal, including humans, in need thereof. All of the con-pounds of Formula (I) are useful in the method of inhibiting or mediating the enzymatic or catalytic activity of PDE IV and in treatment of disease states mediated thereby.
  • salts of the instant compounds where they can be prepared, are also intended to be covered by this invention. These salts will be ones which are acceptable in their application to a pharmaceutical use. By that it is meant that the salt will retain the biological activity of the parent compound and the salt will not have untoward or deleterious effects in its
  • Preferred compounds are as follows:
  • R 1 is an alkyl substituted by 1 or more halogens
  • the halogens are preferably fluorine and chlorine, more preferably a C 1-4 alkyl substituted by 1 or more fluorines.
  • the preferred halo-substituted alkyl chain length is one or two carbons, and most preferred are the moieties -CF 3 , -CH 2 F, -CHF 2 , -CF 2 CHF 2 , -CH 2 CF 3 , and - CH 2 CHF 2 .
  • R 1 substitutents for the compounds of Formula (I) are CH 2 - cyclopropyl, CH 2 -C 5-6 cycloalkyl, C 4-6 cycloalkyl unsubstituted or substituted with OHC 7-11 polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C 1-2 alkyl unsubstituted or substituted by 1 or more fluorines,
  • R 1 term contains the moiety (CR 4 R 5 )
  • the R 4 and R 5 terms are independendy hydrogen or alkyl. This allows for branching of the individual methylene units as (CR 4 R 5 ) n or (CR 4 R 5 ) m ; each repeating methylene unit is independent of the other, e.g., (CR 4 R 5 ) n wherein n is 2 can be -CH 2 CH(-CH 3 )-, for instance.
  • hydrocarbon can unsubstituted or be substituted by fluorine independent of each other to yield, for instance, the preferred R 1 substitutions, as noted above.
  • R 1 is a C 7- 11 polycycloalkyl
  • examples are bicyclo[2.2.1]-heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo[5.2.1.0 2, 6 ]decyl, etc. additional examples of which are described in Saccamano et al., WO 87/06576, published 5 November 1987.
  • W is preferably alkyl, alkenyl or alkynyl of 3 to 5 carbon atoms, and where it is alkenyl or alkynyl, that one or two double or triple bonds be present It is most preferred that W is ethynyl or 1,3-butadiynyl.
  • Z is preferably OR 14 , OR 15 , SR 14 , S(O) m 'R 7 , S(O) 2 NR 10 R 14 , NR 10 R 14 , NR 14 C(O)R 9 , NR 10 C(O)R 14 , NR 10 C(O)OR 7 , NR 10 C(O)NR 10 R 14 ,
  • NR 10 C(NR 10 )NR 10 R 14 NR 10 C(O)C(O)NR 10 R 14 , or NR 10 C(O)C(O)OR 14 .
  • Preferred X groups for Formula (I) are those wherein X is YR 2 and Y is oxygen.
  • the preferred X 2 group for Formula (I) is that wherein X 2 is oxygen.
  • the preferred X 3 group for Formula (I) is that wherein X3 is hydrogen.
  • Preferred R 2 groups, where applicable, is a C 1-2 alkyl unsubstituted or substituted by 1 or more halogens.
  • the halogen atoms are preferably fluorine and chlorine, more preferably fluorine.
  • R 2 groups are those wherein R 2 is mediyl, or the fluoro substituted alkyls, specifically a C 1-2 alkyl, such as a -CF 3 , -CHF 2 , or -CH 2 CHF 2 moiety. Most preferred are the -CHF 2 and -CH 3 moieties.
  • R 7 moieties include unsubstituted or substituted -(CH 2 ) 0-2 (2-, 3- or 4-pyridyl), (CH 2 ) 1-2 (2-imidazolyl), (CH 2 ) 2 (4-moapholinyl), (CH 2 ) 2 (4-piperazinyl), (CH 2 ) 1-2 (2-thienyl), (CH 2 ) 1-2 (4-thiazolyl), unsubstituted or substituted pyrimidinyl, and substituted or unsubstituted (CH 2 ) 0-2 phenyl.
  • Preferred rings when R 10 and R 11 in the moiety -NR 10 R 11 together with the nitrogen to which they are attached form a 5 to 7 membered ring comprised of carbon or carbon and at least one heteroatom selected from O, N, or S include, but are not limited to 1-imidazolyl, 2-(R 8 )-1-imidazolyl, 1-pyrazolyl, 3-(R 8 )-1-pyrazolyl, 1-triazolyl, 2-triazolyl, 5-(R 8 )-1-triazolyl, 5-(R 8 )-2-triazolyl, 5-(R 8 )-1-tetrazolyl, 5-(R 8 )-2-tetrazolyl, 1-tetrazolyl, 2-tetrazloyl, morpholinyl, piperazinyl, 4-(R 8 )-1-piperazinyl, or pyrrolyl ring.
  • R 10 and R 14 in the moiety -NR 10 R 14 together with the nitrogen to which they are attached may form a 5 to 7 membered ring comprised of carbon or carbon and at least one heteroatom selected from O, N, or S include, but are not limited to 1-imidazolyl, 1-pyrazolyl, 1-triazolyl, 2-triazolyl, 1-tetrazolyl,
  • substitutions includes, but is not limited to, 2-(R 7 )-1-imidazolyl, 4-(R 7 )-1-imidazolyl, 5-(R 7 )-1-imidazolyl, 3-(R 7 )-1-pyrazolyl, 4-(R 7 )-1-pyrazolyl, 5-(R 7 )-1-pyrazolyl, 4-(R 7 )-2-triazolyl, 5-(R 7 )-2-triazolyl, 4-(R 7 )-1-triazolyl, 5-(R 7 )-1-triazolyl,
  • R 7 5-(R 7 )-1-tetrazolyl, and 5-(R 7 )-2-tetrazolyl.
  • Applicable nitrogen substitution by R 7 includes, but is not limited to, 1-(R 7 )-2-tetrazolyl, 2-(R 7 )-1-tetrazolyl, 4-(R 7 )-1-piperazinyl, Where applicable, the ring may be substituted one or more times by R 7 .
  • Preferred groups for NR 10 R 14 which contain a heterocyclic ring are 5-(R 14 )-1-tetrazolyl, 2-(R 14 )-1-imidazolyl, 5-(R 14 )-2-tetrazolyl, 4-(R 14 )-1-piperazinyl, or 4-(R 15 )-1-piperazinyl.
  • Preferred rings for R 13 include (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl),
  • the heterocyclic ring itself may be unsubstituted or substituted by R 8 on an available nitrogen or carbon atom, such as 1-(R 8 )-2-imidazolyl, 1-(R 8 )-4-imidazolyl, 1-(R 8 )-5-imidazolyl,
  • R 1 is -CH 2 - cyclopropyl, -CH 2 -C 5-6 cycloalkyl, -C 4-6 cycloalkyl unsubstituted or substituted by OH, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or -C 1-2 alkyl unsubstituted or substituted by 1 or more fluorines, and -(CH 2 ) 2-4 OH;
  • R 2 is methyl or fluorosubstituted alkyl, W is ethynyl or 1,3-butadiynyl;
  • R 3 is R 7 where R 7 is an unsubstituted or substituted aryl or heteroaryl ring,
  • X is YR 2
  • Z is OR 14 , OR 15 , NR 10 R 14 , or NR 14 C(O)R 9 .
  • R 1 is -CH 2 -cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF 2 H
  • X is YR 2
  • Y is oxygen
  • X 2 is oxygen
  • X 3 is hydrogen
  • R 2 is CF 2 H or methyl
  • W is ethynyl or 1,3-butadiynyl
  • R 3 is a substituted or unsubstituted pyrimidinyl ring.
  • the parent compound dissolved in a suitable solvent, is treated with an excess of an organic or inorganic acid, in the case of acid addition salts of a base, or an excess of organic or inorganic base where the molecule contains a COOH for example.
  • compositions of the present invention comprise a
  • compositions may be made up as a solid, liquid or in a gaseous form. Or one of these three forms may be transformed to another at the time of being administered such as when a solid is delivered by aerosol means, or when a liquid is delivered as a spray or aerosol.
  • compositions and the pharmaceutical carrier or diluent will, of course, depend upon the intended route of administration, for example parenterally, topically, orally or by inhalation.
  • the pharmaceutical composition will be in the form of a cream, ointment liniment, lotion, pastes, aerosols, and drops suitable for topical administration.
  • the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampule or an aqueous or non-aqueous liquid suspension.
  • a sterile injectable liquid such as an ampule or an aqueous or non-aqueous liquid suspension.
  • the pharmaceutical composition will be in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup, liquid, or emulsion.
  • examples of appropriate pharmaceutical carriers or diluents include: for aqueous systems, water, for non-aqueous systems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid parafins and mixtures thereof wit water; for solid systems, lactose, kaolin and mannitoL and for aerosol systems, dkhlorodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide.
  • the instant compositions may include other ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do not have a detrimental effect on the therapeutic action of the instant compositions.
  • the amount of carrier or diluent will vary but preferably will be the major proportion of a suspension or solution of the active ingredient
  • the diluent is a solid it may be present in lesser, equal or greater amounts than the solid active ingredient
  • a compound of formula I is administered to a subject in a composition comprising a nontoxic amount sufficient to produce an inhibition of the symptoms of a disease in which leukotrienes are a factor.
  • Topical formulations will contain between about 0.01 to 5.0% by weight of the active ingredient and will be applied as required as a preventative or curative agent to the affected area.
  • me dosage of the composition is selected from the range of from 50 mg to 1000 mg of active ingredient for each administration. For convenience, equal doses will be administered 1 to 5 times daily with the daily dosage regimen being selected from about 50 mg to about 5000 mg.
  • Compounds of Formula (I) may be prepared by the processes disclosed herein which comprise reacting a terminal acetylene, wherein Z represents Z as defined in relation to Formula (I) or a group convertible to Z, as, e.g., compound 1-Scheme 1. with an appropriate halide, R 3 X, wherein R 3 represents R 3 as defined in relation to Formula (I) or a group convertible to R 3 , in the presence of a suitable catalyst, such as a copper (I) halide and a bivalent or zerovalent palladium compound in the presence of, e.g., triphenylphosphine, in a suitable solvent, such as an amine, as in the pr° Cedure of Brandsma et al. (Syn.
  • a suitable catalyst such as a copper (I) halide and a bivalent or zerovalent palladium compound in the presence of, e.g., triphenylphosphine, in a suitable solvent, such as an amine, as in
  • compounds of the Formula (I), wherein Z and R 3 represent Z and R 3 as defined in relation to Formula (I) or a group convertible to Z or R 3 may be prepared from the corresponding ketones as, e.g., compound 1 -Scheme 2. by the synthetic pr° Cedures described in PCT application number PCT/US93/01990 and PCT/US93/02325 published as WIPO publication number WO93/19750 .
  • oxidative carbonylation of a terminal acetylene as, e.g., compound 1-Scheme 3. using an appropriate metal salt such as a copper salt with a catalytic amount of a palladium salt, in the presence of a suitable base as an acid trap, such as sodium acetate, in a suitable alcohol, such as methanol, then provides the compound of the Formula 2-Scheme 3: such compounds may men be converted to other compounds of the Formula (I) by manipulation of the ketone as described above and by independent manipulation of the carboxylic ester moiety using standard txansesterification or amidation conditions. Syntheses of such ketone starting materials are described in published PCT application PCT/US93/02O45 (WIPO publication number WO
  • PCT/US93/001990 (WIPO publication number WO 93/19748) or PCT/US93/02325 (WIPO publication number WO/93/19750) in 1,2-dimethoxyethane (5 mL) under an argon atmosphere was added sodium borohydride (0.08 g, 2.2 mmol) and the mixture was stirred at room temperature for 0.5 h. Water was added, the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated.
  • triphenylphosphine The mixture was refluxed for 5 h, then concentrated in vacua. The residue was diluted with ethyl acetate (100 mL), was washed with brine, was dried (MgSO 4 ) and was evaporated. Purification by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, foliowed by trituration from ether/hexanes, provided the tide compound as white solid (0.09 g, 58%), m.p. 90-91° C.
  • Methyl 3-iodobenzoate was prepared by standard chemistry well known to those versed in the an and is a white solid, cap.40-41° C
  • the enantiomer was prepared in a similar manner, starting with the compound from Example 3 (E2), as a white solid, m.p. 97-99° C.
  • the enantiomer was prepared in a similar manner, starting with the compound from Example 3 (E2), as a white solid, m.p. 117-119° C.
  • the enantiomer was prepared in a similar manner, starting with the compound from Example 3 (E2), as a white solid, mp. 122-123° C.
  • the enantiomer was prepared in similar manner, starting with the compound from Example 3 (E2), as a clear yellow glass.
  • the enantiomer was prepared in a similar manner, starting with the compound from Example 3 (E2), as a yellow solid, mp. 46-48° C.
  • 3-acetamido-1-iodobenzene was prepared by standard chemistry well known to those versed in the an and is a white solid, mp. 117-118° C.
  • 1-iodo-3-methanesulfonamidobenzene was prepared by standard chemistry well known to those versed in the an and is light-pink solid, mp. 102-103° C.
  • 1-iodo-3-trifluoroacetamidobenzene was prepared by standard chemistry well known to those versed in the art and is a white solid, m.p. 120-121° C
  • triphenylphosphine (1.25 g, 4.77 mmol) in tetrahydrofuran (32 mL) was dropwise added diethyl azodicarboxylate (0.75 mL, 4.77 mmol), and the solution was stirred under an argon atmosphere at room temperature for 2 h. Evaporation and purification by flash chromatography, eluting with 2:8 ethyl acetate hexanes, provided the intermediate phthalimide (1.43 g) as a waxy white solid, mp 45-52° C.
  • hydroxide:methanol:dichloromethane provided cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexyl-1-amine] as a colorless oil (0.71 g, 72%).
  • dichloromethane (5 mL) at 0° C under an argon atmosphere was added trifluoroacetic acid (0.60 mL, 7.89 mmol). The reaction was stirred at room temperature for 6 h, was cooled to 0° C, quenched with sodium bicarbonate, was diluted with water, was extracted with three times dichloromethane, was dried (magnesium sulfate) and was evaporated.
  • cyanoborohydride (0.17 g, 2.63 mmol) and several 4 ⁇ molecular sieves in methanol (10 mL) was stirred under an argon atmosphere at room temperature for 3 days.
  • hydroxide:methanol:dichloromethane provided cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexyl-1-amine] as a colorless glass (0.11 g, 0.24 mmol, 69%).
  • This intermediate was dissolved in acetone (0.5 mL) and was added to a solution of cyclohexylsulfamic acid (0.045 g, 0.24 mmol) in acetone (1 mL).
  • 5-Bromo-2-propionamidopyrimidine was prepared by standard chemistry weli known to those versed in the an and was a white solid, mp 161-164° C.
  • hydroxide:methanol:dichloromethane provided trans-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl-1-amine] as a very viscous, colorless oil (0.13 g, 0.33 mmoL 95%).
  • This intermediate was dissolved in acetone (0.5 mL) and treated with a solution of cyclohexylsulfamic acid (0.059 g, 0.33 mmol) in acetone (1.0 mL). Dilution with ether and filtration, followed by trituration from dichloromethane/hexanes provided the tide compound as a white solid mp >230° C (dec.).
  • cyclohexylsulfamate salt cis-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexyl-1-amine], cyclohexylsulfamate salt cis-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl-1-amine], cyclohexylsulfamate salt is prepared in the same manner as trans-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl-1- amine], except starting from cis -[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-e
  • inhibitory effect of compounds of Formula (I) on in vitro TNF production by human monocytes may be determined by the protocol as described in Badger et al.,
  • Example 1 demonstrated a positive in vivo response in reducing serum levels of TNF induced by the injection of endotoxin.
  • the phosphodiesterase inhibitory activity and selectivity of the compounds of Formula (I) can be determined using a battery of five distinct PDE isozymes.
  • the tissues used as sources of the different isozymes are as follows: 1) PDE lb, porcine aorta; 2) PDE Ic, guinea-pig heart; 3) PDE III, guinea-pig heart; 4) PDE IV, human monocyte; and 5) PDE V (also called "la”), canine trachealis.
  • PDEs la, lb, Ic and m are partially purified using standard chromatographic techniques [Torphy and
  • PDE IV is purified to kinetic homogeneity by the sequential use of anion-exchange foliowed by heparin-Sepharose chromatography [Torphy et al., J. Biol. Chem., 267:1798-1804, 1992].
  • Phosphodiesterase activity is assayed as described in the protocol of Torphy and

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Abstract

La présente invention concerne de nouveaux monomères de 4,4-(disubstitué)cyclohexan-1-oles et leurs composés apparentés, ainsi que les compositions pharmaceutiques contenant ces composés. Cette invention concerne également leur utilisation dans le traitement d'allergies et de maladies inflammatoires, ainsi que pour inhiber la production de facteur de nécrose tumorale (TNF).
PCT/US1995/016711 1994-12-23 1995-12-21 Monomeres de 4,4-(disubstitue)cyclohexan-1-oles et composes apparentes WO1996019988A1 (fr)

Priority Applications (14)

Application Number Priority Date Filing Date Title
DE69534518T DE69534518D1 (de) 1994-12-23 1995-12-21 Monomere der 4,4-(disubstituierten)cyclohexan-1-ole und verwandte verbindungen
UA97066495A UA48157C2 (uk) 1994-12-23 1995-12-21 Мономери 4,4-(двозаміщених)циклогексан-1-олів, фармацевтична композиція та спосіб лікування астми
AT95944363T ATE306260T1 (de) 1994-12-23 1995-12-21 Monomere der 4,4-(disubstituierten)cyclohexan-1- ole und verwandte verbindungen
NZ301096A NZ301096A (en) 1994-12-23 1995-12-21 4,4-(disubstituted)cyclohexan-1-ol monomer and related derivatives; medicaments containing them
SK795-97A SK79597A3 (en) 1994-12-23 1995-12-21 4,4-(disubstituted)cyclohexan-1-ols monomers and pharmaceutical compositions containing same
JP8520529A JPH10511658A (ja) 1994-12-23 1995-12-21 ４，４−（二置換）シクロヘキサン−１−オール単量体および関連する化合物
BR9510257A BR9510257A (pt) 1994-12-23 1995-12-21 Monômeros ciclohexan-1-óis 4,4-(di-substituidos) e compostos relacionados
MX9704729A MX9704729A (es) 1994-12-23 1995-12-21 Monomeros de 4,4-(disustituido)ciclohexan-1-oles y compuestos relacionados.
US08/860,287 US5891883A (en) 1995-12-21 1995-12-21 4,4-(disubstituted)cyclohexan-1-ols monomers and related compounds
EP95944363A EP0794774B1 (fr) 1994-12-23 1995-12-21 Monomeres de 4,4-(disubstitue)cyclohexan-1-oles et composes apparentes
AU46433/96A AU703246C (en) 1994-12-23 1995-12-21 4,4-(disubstituted)cyclohexan-1-ols monomers and related compounds
FI972676A FI972676A (fi) 1994-12-23 1997-06-19 4,4-(disubstituoitu)sykloheksan-olimonomeerejä ja vastaavia yhdisteitä
NO972906A NO972906L (no) 1994-12-23 1997-06-20 4,4-(Disubstituerte)cykloheksan-1-ol-monomerer og beslektede forbindelser
BG101716A BG62034B1 (bg) 1994-12-23 1997-07-01 4,4-(дизаместени)циклохексан-1-олови мономери и сроднисъединения

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US36350694A 1994-12-23 1994-12-23
US08/363,506 1994-12-23

Publications (1)

Publication Number Publication Date
WO1996019988A1 true WO1996019988A1 (fr) 1996-07-04

Family

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Application Number Title Priority Date Filing Date
PCT/US1995/016711 WO1996019988A1 (fr) 1994-12-23 1995-12-21 Monomeres de 4,4-(disubstitue)cyclohexan-1-oles et composes apparentes

Country Status (21)

Country Link
EP (1) EP0794774B1 (fr)
JP (1) JPH10511658A (fr)
CN (1) CN1090020C (fr)
AT (1) ATE306260T1 (fr)
BG (1) BG62034B1 (fr)
BR (1) BR9510257A (fr)
CA (1) CA2208444A1 (fr)
CZ (1) CZ196097A3 (fr)
DE (1) DE69534518D1 (fr)
DZ (1) DZ1959A1 (fr)
FI (1) FI972676A (fr)
HU (1) HUT77350A (fr)
MA (1) MA23755A1 (fr)
MX (1) MX9704729A (fr)
NO (1) NO972906L (fr)
NZ (1) NZ301096A (fr)
PL (1) PL320996A1 (fr)
SK (1) SK79597A3 (fr)
UA (1) UA48157C2 (fr)
WO (1) WO1996019988A1 (fr)
ZA (1) ZA9510878B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0828493A1 (fr) * 1995-05-31 1998-03-18 Smithkline Beecham Corporation Monomeres de 4,4-cyclohexan(disubstitue)-1-ols et composes s'y rapportant
EP1202955A2 (fr) * 1999-08-10 2002-05-08 SmithKline Beecham Corporation 4,4-diaryl cyclohexanes substitues en 1-4

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5449687A (en) * 1992-04-02 1995-09-12 Smithkline Beecham Corporation 4-phenyl-1,2-cyclohexyl derivatives and anti-inflammatory compositions and methods thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993019751A1 (fr) * 1992-04-02 1993-10-14 Smithkline Beecham Corporation Composes utilisables dans le traitement des maladies inflammatoires et dans l'inhibition de la production du facteur de necrose tumorale
AR004471A1 (es) * 1995-05-31 1998-12-16 Smithkline Beecham Corp Compuestos de ciclohexan-1-ol-4,4-disustituidos, utiles en el tratamiento de enfermedades alergicas e inflamatorias y composiciones farmaceuticas que lascontienen

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5449687A (en) * 1992-04-02 1995-09-12 Smithkline Beecham Corporation 4-phenyl-1,2-cyclohexyl derivatives and anti-inflammatory compositions and methods thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0828493A1 (fr) * 1995-05-31 1998-03-18 Smithkline Beecham Corporation Monomeres de 4,4-cyclohexan(disubstitue)-1-ols et composes s'y rapportant
EP0828493A4 (fr) * 1995-05-31 1998-09-02 Smithkline Beecham Corp Monomeres de 4,4-cyclohexan(disubstitue)-1-ols et composes s'y rapportant
EP1202955A2 (fr) * 1999-08-10 2002-05-08 SmithKline Beecham Corporation 4,4-diaryl cyclohexanes substitues en 1-4
EP1202955A4 (fr) * 1999-08-10 2004-02-11 Smithkline Beecham Corp 4,4-diaryl cyclohexanes substitues en 1-4

Also Published As

Publication number Publication date
CZ196097A3 (cs) 1998-01-14
HUT77350A (hu) 1998-03-30
CN1090020C (zh) 2002-09-04
BR9510257A (pt) 1997-11-04
NO972906D0 (no) 1997-06-20
JPH10511658A (ja) 1998-11-10
EP0794774B1 (fr) 2005-10-12
ATE306260T1 (de) 2005-10-15
DZ1959A1 (fr) 2002-02-17
EP0794774A1 (fr) 1997-09-17
BG62034B1 (bg) 1999-01-29
ZA9510878B (en) 1997-06-17
UA48157C2 (uk) 2002-08-15
NZ301096A (en) 1999-01-28
CN1175210A (zh) 1998-03-04
MX9704729A (es) 1997-10-31
MA23755A1 (fr) 1996-07-01
BG101716A (en) 1998-03-31
SK79597A3 (en) 1998-01-14
FI972676A (fi) 1997-08-19
AU703246B2 (en) 1999-03-25
NO972906L (no) 1997-08-15
AU4643396A (en) 1996-07-19
EP0794774A4 (fr) 1998-04-29
DE69534518D1 (de) 2006-02-23
FI972676A0 (fi) 1997-06-19
PL320996A1 (en) 1997-11-24
CA2208444A1 (fr) 1996-07-04

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